Mitochondrial methionyl N-formylation affects steady-state levels of oxidative phosphorylation complexes and their organization into supercomplexes

Arguello, Tania; Köhrer, Caroline; RajBhandary, Uttham L.; Moraes, Carlos T.

doi:10.1074/jbc.ra118.003838

Cited by 18 publications

(17 citation statements)

References 33 publications

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“…Studies using a Mtfmt knockout mouse fibroblast model lacking exon 4 in MTFMT demonstrated that MTFMT is not an absolute requirement for initiation of translation and elongation of mitochondrial protein synthesis in mice but deficiency of this protein results in reduced efficiency of this process and downstream oxidative phosphorylation defects. 24 This may contribute to the overall milder disease course observed in the MTFMT-related mitochondrial disease presented here compared with typical LS.…”

Section: Discussionmentioning

confidence: 79%

Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis

Hayhurst

Coo

Piekutowska‐Abramczuk

et al. 2019

Ann Clin Transl Neurol

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Objectives Mitochondrial methionyl‐tRNA formyltransferase (MTFMT) is required for the initiation of translation and elongation of mitochondrial protein synthesis. Pathogenic variants in MTFMT have been associated with Leigh syndrome (LS) and mitochondrial multiple respiratory chain deficiencies. We sought to elucidate the spectrum of clinical, neuroradiological and molecular genetic findings of patients with bi‐allelic pathogenic variants in MTFMT. Methods Retrospective cohort study combining new cases and previously published cases. Results Thirty‐eight patients with pathogenic variants in MTFMT were identified, including eight new cases. The median age of presentation was 14 months (range: birth to 17 years, interquartile range [IQR] 4.5 years), with developmental delay and motor symptoms being the most frequent initial manifestation. Twenty‐nine percent of the patients survived into adulthood. MRI headings in MTFMT pathogenic variants included symmetrical basal ganglia changes (62%), periventricular and subcortical white matter abnormalities (55%), and brainstem lesions (48%). Isolated complex I and combined respiratory chain deficiencies were identified in 31% and 59% of the cases, respectively. Reduction of the mitochondrial complex I and complex IV subunits was identified in the fibroblasts (13/13). Sixteen pathogenic variants were identified, of which c.626C>T was the most common. Seventy‐four percent of the patients were alive at their last clinical review (median 6.8 years, range: 14 months to 31 years, IQR 14.5 years). Interpretation Patients that harbour pathogenic variants in MTFMT have a milder clinical phenotype and disease progression compared to LS caused by other nuclear defects. Fibroblasts may preclude the need for muscle biopsy, to prove causality of any novel variant.

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Section: Discussionmentioning

confidence: 79%

Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis

Hayhurst

Coo

Piekutowska‐Abramczuk

et al. 2019

Ann Clin Transl Neurol

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“…This indicated that HPGylated mt-tRNA Met could both initiate synthesis as well as contribute to elongation. It is tempting to infer that a subset of HPGylated mt-tRNA Met could have been formylated by mitochondrial methionyl-tRNA formyltransferase, mimicking the endogenous initiation mechanism ( 33 ), but recent data suggest that, under certain circumstances, initiation in mitochondria may occur without formylation of an initiating mt-tRNA Met ( 34 ).…”

Section: Resultsmentioning

confidence: 99%

High-resolution imaging reveals compartmentalization of mitochondrial protein synthesis in cultured human cells

Zorkau

Albus

Berlinguer‐Palmini

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Human mitochondria contain their own genome, mitochondrial DNA, that is expressed in the mitochondrial matrix. This genome encodes 13 vital polypeptides that are components of the multisubunit complexes that couple oxidative phosphorylation (OXPHOS). The inner mitochondrial membrane that houses these complexes comprises the inner boundary membrane that runs parallel to the outer membrane, infoldings that form the cristae membranes, and the cristae junctions that separate the two. It is in these cristae membranes that the OXPHOS complexes have been shown to reside in various species. The majority of the OXPHOS subunits are nuclear-encoded and must therefore be imported from the cytosol through the outer membrane at contact sites with the inner boundary membrane. As the mitochondrially encoded components are also integral members of these complexes, where does protein synthesis occur? As transcription, mRNA processing, maturation, and at least part of the mitoribosome assembly process occur at the nucleoid and the spatially juxtaposed mitochondrial RNA granules, is protein synthesis also performed at the RNA granules close to these entities, or does it occur distal to these sites? We have adapted a click chemistry-based method coupled with stimulated emission depletion nanoscopy to address these questions. We report that, in human cells in culture, within the limits of our methodology, the majority of mitochondrial protein synthesis is detected at the cristae membranes and is spatially separated from the sites of RNA processing and maturation.

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“…Despite the ancient origins of our dependence on mitochondria, why are mitochondria still recognized as foreign by the immune system? Formylation of mitochondrial proteins is required for their function, as deletion of formyl-transferase leads to decreased efficiency of oxidative phosphorylation (Tucker, Hershman et al 2011, Arguello, Köhrer et al 2018. Perhaps inflammatory activation by formyl-peptides plays a role in host defense.…”

Section: Discussionmentioning

confidence: 99%

Pink1-mediated mitophagy in the endothelium releases proteins encoded by mitochondrial DNA and activates neutrophil responses

Gajwani

Wang

Srivastava

et al. 2022

Preprint

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Given their ancient evolutionary origins, eukaryotic mitochondria possess multiple vestiges of their prokaryotic ancestors. One such factor is the N-terminal formylation of proteins encoded by mitochondrial DNA. N-formylated proteins are also released by bacteria and trigger activation of immune cells such as neutrophils. Growing evidence indicate that circulating levels of mitochondrial formyl proteins are elevated in the serum of patients with excessive inflammatory responses and trigger neutrophil activation like their bacterial counterparts. However, the cellular source of these proteins, and the mechanism by which they are released into the circulation is not known. In this study, we have identified vascular endothelial cells as a source of mitophagy induced release of formyl proteins in response to inflammatory mediators in vitro. Mechanistically, endothelial mitophagy required activation of the Pink1 pathway. Using liposomal delivery of sgRNA targeting Pink1 in mice expressing endothelial-specific Cas9, we developed a mouse model in which Pink1 is specifically depleted in the endothelium. Deletion of endothelial Pink1 was remarkably protective in endotoxin-induced lung inflammation, resulting in reduced neutrophil infiltration and significantly reduced death in mice. We thus propose that endothelial cells upregulate pro-inflammatory mitophagy in response to inflammation, leading to release of mitochondrial formyl peptides and detrimental neutrophil recruitment into the lung.

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Mitochondrial methionyl N-formylation affects steady-state levels of oxidative phosphorylation complexes and their organization into supercomplexes

Cited by 18 publications

References 33 publications

Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis

Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis

High-resolution imaging reveals compartmentalization of mitochondrial protein synthesis in cultured human cells

Pink1-mediated mitophagy in the endothelium releases proteins encoded by mitochondrial DNA and activates neutrophil responses

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